JPH11509226A - Composition comprising D-threo-methylphenidate and another medicament - Google Patents

Abstract

(57) Abstract: methylphenidate therapy and to treat a subject undergoing concomitant therapy with another medicament interfere with receiving or P ₄₅₀ to P ₄₅₀ metabolism, methylphenidate d- threo - Mechirufeni How to be a date.

Description

Description: FIELD OF THE INVENTION The present invention relates to a novel composition comprising methylphenidate and another medicament and d-threo-methylphenidate (Hereinafter abbreviated as d-tmp). BACKGROUND OF THE INVENTION Methylphenidate is a known drug (albeit a controlled substance). It has been used primarily to treat hyperactivities children. Methylphenidate is a chiral molecule. Although the properties of the enantiomer have been studied to some extent, the drug is still administered as a racemate. Generally, d-tmp is considered an active substance, and its enantiomer (l-tmp) is believed to be metabolized faster. Methylphenidate is often administered in combination with other medicaments. It is known that co-administration of two drugs that act or are metabolized through the same metabolic pathway can cause the drug to interact and block that pathway. Racemic methylphenidate interacts clinically with various drugs, such as tricyclic antidepressants (TCAs), and administration of TCA when co-administered to prevent drug interactions It is known that the amount needs to be reduced (Physicians Desk Reference, Guide to Drug Interactions, 1994). It is generally believed that each enantiomer of a chiral therapeutic drug exhibits a different toxicological aspect, one of which is usually responsible for the toxic effects of drug interactions; Schweizerischer, Aliens. -See Medizilliche Wochenschrift (Schweiz. Med. Wochenschr.) 120 (5): 131-134 (1990). Each enantiomer has become this foundation, the path of the enzyme metabolism, e.g. cytochrome P ₄₅₀ routes to show different advantages, therefore is that the co-administered medications such is blocked by the different sites of metabolism. The surprisingly spirit of the invention which should, d-tmp be l-tmp also been found to interfere with the metabolism of other pharmaceutical by cytochrome P ₄₅₀ system in the microsomes of human as well. Furthermore, the racemate has been shown to have stronger interfering properties than any of the enantiomers, suggesting that there is an interaction between the enantiomers. Would significantly reduce interference with P ₄₅₀ isozymes by administering a substantially l-tmp contains no d-tmp. This is a welcome effect for patients receiving co-administration of other drugs. In order to avoid the danger of toxicity due to drug-drug interactions, the present invention relates to the administration of d-tmp with such other drugs. The two medicaments used in the present invention may be administered sequentially, jointly or simultaneously, using the same or different means. This finding is surprisingly based on data indicating that there is less toxin in the liver of mice than when racemic methylphenidate is administered by administering d-tmp, possibly due to liver cytochromes. This may be due to the lesser degree of interference with the _P450 enzyme. The experiment and its data are summarized as follows. The present invention is thus particularly useful in individuals having low efficiency of the relevant enzymes or using cross-reactive medicaments, such as SSRIs, for the treatment of anxiety and depression. DETAILED DESCRIPTION OF THE INVENTION The d-tmp used in the present invention is substantially free of l-tmp and has, for example, an enantiomeric excess (ee) of at least 70%, preferably at least 90%, more preferably at least 95%. is there. d-tmp may be substantially enantiopure. d-tmp may be used in the form of any suitable salt, for example the hydrochloride. As described above, d-tmp and other drugs may be administered independently. The invention is not limited to a particular route of administration, and it will generally be preferred that each medicament be administered by its respective preferred route of administration. Thus, d-tmp may be administered in the same manner as a racemic methylphenidate, for example, as a sustained release dosage form, such as a coated tablet. More preferably, a co-pending co-filed patent application filed on the same day as "a sustained release form of methylphenidate" [assigned to Chiloscience and based on UK Patent Application No. 9514451.5] Priority claim]. The relevant content of that application is part of the present invention. The benefits of using d-tmp are also described herein, including linear kinetics at clinically relevant dose ranges, reduced contact with modulators, (anorexia, insomnia, abdominal pain and headache. Reduced side reactions, low hepatotoxicity, low abuse potential, low C _max , low active substance concentration even when chewed, low inter-patient variability, and It may include a reduction in variability between subjects. By controlling the nature of the dosage form, it is possible to control the in vitro solubility, thereby matching the drug release profile of the United States National Drug Collection (NF) in the case of methylphenidate hydrochloride or It is possible to go beyond that. Further, when administered to a healthy subject, the amount of d-tmp in serum should be at least 50% of _Cmax for at least 8 hours, for example, 8-16 hours, 8-12 hours, or 8-10 hours. Can be. Thus, for example, a shorter release period may be preferred, or a different period of time before the concentration in the serum falls below some different magnitude relative to _Cmax . In addition, after administration in the morning, the amount in the serum may be controlled so as to maintain a high concentration during the day but decrease during the night so as not to adversely affect the sleep pattern. The dosage form of the invention may be in unit dosage form such as a tablet, capsule or suspension. The sustained release dosage form may be in the form of a matrix, coating, reservoir, osmotic pressure, ion exchange or density conversion. Sustained release dosage forms may include a soluble polymer coating that dissolves or gradually disintegrates after administration. Alternatively, it may be an insoluble coating, for example a polymer, through which the active ingredient permeates, for example from a reservoir, diffuses, for example through a porous matrix, or undergoes osmotic conversion. You may. Still other sustained release dosage forms include those in which the active ingredient is diffused or passed through due to density conversion, for example, a dosage form that changes from a particulate to a gel upon administration. Ionic resins can also be used, wherein the active ingredient is released by ion exchange, in which case the release rate can be controlled by using the medicament in cationic or anionic form. In the present invention, an agent which is chew-resistant, for example, a fine particle which is coated so that it does not immediately release the active ingredient when chewed or chewed due to its firmness. Preferably, a mold is used. The dosage forms of the present invention having improved release characteristics may also be suitable for administering racemic methylphenidate. In addition, many of the effects, advantages, etc., described herein also apply to immediate release dosage forms. Various effects may be due to using d-tmp and / or using it without l-tmp. The other drug may be administered in combination with methylphenidate. Alternatively, they may be administered in other dosage forms by an appropriate route of administration. The usual dosing parameters may be employed, ie those known to the person skilled in the art or actually applied by the person skilled in the art. For example, a daily dose of d-tmp may be 5-60 mg, but will be selected according to the age, weight and health of the subject, and other factors which are ordinarily considered by those skilled in the art. d-tmp is used primarily for the treatment of hyperactive children, as a stimulant in cancer patients treated with narcotic analgesics, or in the treatment of depressive symptoms (eg in AIDS patients), threatening shopping disease May be administered to treat sleep attacks or excessive sleep. These subjects generally suffer from other diseases that require medicine. The invention particularly uses such other medicaments, such as those applied to treat CNS disorders (eg depression)-which may be tricyclic antidepressants or SSRIs. Used in cases. Thus, the other medicament may be of the same mode of action or may have a similar CNS activity. As alternative, or in addition, the other medicament for use in the present invention is similar to decreased metabolism and l-tmp, for example those that cause a reduction in P ₄₅₀ cytochrome through metabolism, which interfere with l-tmp metabolism Or any that has metabolism interfered by l-tmp. There are a number of drugs that may interfere with methylphenidate. An example is an antisedative. Certain pharmaceutical compounds important are those that metabolism is known to occur through cytochrome P ₄₅₀ path. For example, clomipramine, desipramine, indolamin, imipramine, imipramine, phen formin and tropisetron cause hydroxylation of aromatics; amiflamin ) Causes demethylation at the N-position, amitriptyline and nortriptyline cause hydroxylation of benzyl; codeine, dextromethorphan, dihydrocodein, dihydrocodeine, hydroc Done), norcodeine and oxycodeone cause demethylation at the O-position; ethylmorphine causes deethylation at the O-position; flecainide and methoxyamphetamine Methoxyphenamine causes aromatic hydroxylation and demethylation at the N position; mexiletine and ondansetron cause hydroxylation; perhexyline (Perhexiline) causes aliphatic dehydroxylation and thioridazine (th oridazi ne) will cause the side-chain sulfonated. These are merely examples of pharmaceuticals that use a fixed route. Other important specific pharmaceuticals are cinnarizine, haloperidol, maprotiline, paroxetine, and perphenazine. Particularly important pharmaceuticals known to interact with methylphenidate include amitriptyline, amoxapine, clomipramine, desipramine, dexepamine, imipramine. ), Maprotiline, nortriptyline, protriptyline or tritripramine tricyclic antidepressants (TCAs); phenelzine or selenegine; (Tranylc romine) Monoamine oxidase inhibitors; selective serotonin reabsorption inhibitors (SSRIs) such as fluoxetine, paroxetine or sertroline; antipsychotics such as haloperidol; Anticonvulsants / antiepileptic drugs such as primidone and diphenylhydantoin; anticoagulants such as warfarin; and isocarboxazide (isocarboxamide). metaminolol, phenylbutazone zone), phenylephrine, dopamide, norepinephrine, epinephrine, furazalidone, and lithosigmin in which phosostigmine has been reported. Other medicines. Patients diagnosed with attention-deficit hyperactivity disorder (ADHD; this term is also used here to include attention-deficit disorder), typically children, Are often not required, but often have a concomitant CNA disease (whether diagnosed or not) that indicates a potential need for SSRI or TCA in the future, for example. For such patients the use of d-tmp is indicated in the present invention. Children treated with a combination of imipramine and methylphenidate had side effects, including cognitive and mood deterioration. Lithium significantly reduces the level of arousal-activation, euphoria-grandiosity, and the overall score of manic status after methylphenidate administration. In addition, of the 20 treated with tricyclics in combination with methylphenidate, 3 were removed from the study due to adverse reactions. These side effects included dizziness, orthostatic blood pressure changes, dry mouth, increased anxiety and hypomania. Administering 10 mg / kg baclofen 10 minutes after methylphenidate administration, this completely blocks both methylphenidate-enhancing activity and stereotypic pics in rats within 15-25 minutes. Was done. In the treatment of manic patients, physostigmine and methylphenidate each neutralized the other effect. Racemic methylphenidate on metabolic liver cytochrome P ₄₅₀ route methylphenidate by cytochrome P _450, an experiment was conducted to investigate the effects of d-tm p and l-tmp. Use of a pharmaceutical compound that is known to be characteristic metabolized by certain P _{4 50} isotype as experimental method, corresponding in the human microsomes prepared by the following standard methods "enzyme activity" (the following results Tolbutamide: Knodell et al., Journal of Pharmacology and Experimental Therapeutics (J. Pharmacol. Exp. Thes.) Vol. 241 (Vol. No. 3): 1012-109 (1987); Mephenytoin: Yasnori et al., Journal of Pharmacology and Experimental Therapeutics, Vol. 264 (No. 1): 89- Page 94 (1993); Bufuralol: Kronbach et al., Analytical Biochemistry, Vol. 162: 24-32 (1987); Lauric acid: Okita et al., Methods in E. Zaimoroji, # 206, pp. 432-441 (1991). The relationship of a particular P ₄₅₀ isotype using known standards interfering compounds (see table Results) was confirmed using the indicated inhibitor concentration. Methylphenidate, d-tmp and l-tmp were used at 100 μM. According to the results, it was shown to have a disturbing activity having a similar profile on the liver cytochrome P _{45 0} route Surprisingly the d-tmp and l-tmp. Furthermore, racemic methylphenidate appears to have more interfering activity on certain enzymes than d-tmp or l-tmp. Thus, reduced drug interactions may be due to reduced interfering properties of enzymes in the _P450 pathway.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), UA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AM, AU, AZ, BB , BG, BR, BY, CA, CN, CZ, EE, GB, GE, HU, IL, IS, JP, KE, KG, KP, K R, KZ, LK, LR, LS, LT, LV, MD, MG , MK, MN, MW, MX, NO, NZ, PL, RO, RU, SD, SG, SI, SK, TJ, TM, TR, T T, UA, UG, UZ, VN (72) Inventor Pope, Nicholas Robert             UK, CB 4.4             -Cambridge, Milton Road,             Bridge Science Park, Cairo             Within Science Limited

Claims (1)

[Claims] 1. In treating a condition to which methylphenidate and the other drug are applied respectively, as a combined preparation for simultaneous, separate or sequential use, comprising d-threo-methylphenidate and another drug; pharmaceutical product interfere with or P ₄₅₀ metabolism cause the P ₄₅₀ metabolism. 2. In treating a condition to which methylphenidate and the other drug are applied respectively, d-threo-methylphenidate and another drug are contained as a combined preparation for simultaneous, separate or sequential use, and either drug is used. A product that causes undesirable side reactions, such as toxicity, or enhances it with the other drug. 3. 3. A product according to claim 1 or 2, wherein the other medicament is a tricyclic antidepressant or an antidepressant such as SSRI. 4. 4. Methylphenidate for the treatment of depression, compulsive shopping disease, sleep attacks (narcolepsy), insomnia (insomnia) and attention-deficit hyperactivity disorder. The product according to any of the above. 5. The product according to any one of claims 1 to 4, wherein the patient is an adult. 6. 5. The product of claim 4, wherein the methylphenidate is for treating attention deficit hyperactivity disorder in prepubertal children. 7. 7. The product according to any one of claims 1 to 6 for treating patients suffering from or susceptible to the CNS, for example having anxiety, depressive symptoms or epilepsy. 8. Use of d-threo-methylphenidate for the manufacture of a medicament for treating patients with symptoms to be treated with methylphenidate and patients exhibiting or prone to other CNS disorders. 9. D- for the manufacture of a medicament for use in the treatment of attention deficit hyperactivity disorder in a patient concomitantly receiving treatment with another medicament as defined in any of claims 1 to 3. Use of threo-methylphenidate. 10. Methylphenidate for treating a subject receiving concomitant treatment with methylphenidate treatment and another medicament as defined in any of claims 1 to 3, wherein the methylphenidate is d-threomethylphenidate One way. 11. 11. The method of claim 10, wherein the treatment is defined in any of claims 4-7.